The present invention relates to a process for the preparation of 3,5-bis-(trifluoromethyl)benzoyl chlorides from the corresponding 3,5-dimethylbenzoic acids and to novel 3,5-bis(trihalogenomethyl)- and 3,5-dimethylbenzoyl halides that arise as intermediates in the process. In the text below, 3,5-bis(trifluoromethyl)benzoyl chlorides are also referred to as BTBs.
BTBs are intermediates for the preparation of pharmaceutical and agrochemical active ingredients and photoresist compositions.
The preparation of BTBs from the corresponding 3,5-bis(trifluoromethyl)benzoic acid by chlorination is known (see, for example, J. Med. Chem., 38, 3106 (1995)). This acid can be obtained in two different ways, by
(a) metallizing 1-bromo-3,5-bis(trifluoromethyl)benzene with magnesium or lithium (see Bull. Soc. Chim. Fr., 1962 (587) and Chem. Ber., 129, 233 (1996)) and then reacting with carbon dioxide or, in the presence of a palladium catalyst, with carbon monoxide and water (see JP-OS 09/67,297) or
(b) reacting 3,5-bis(trifluoromethyl)benzene with a mixture of butyllithium and potassium t-butoxide (see Synlett, 1990, 747) or only with butyllithium (see J. Organomet. Chem., 67, 321 (1974)) and then with carbon dioxide.
These processes for the preparation of BTBs are less suitable for the industrial scale because in all cases organometallic compounds have to be prepared and handled, which is possible only with great technological expenditure. Moreover, 3,5-bis(trifluoromethyl)benzene and the corresponding 1-bromo compound can be prepared only by a complex route. Added to this is the danger of the exothermic decomposition of meta-trifluoromethyl-substituted phenyl-magnesium and -lithium compounds, which likewise require great expenditure for somewhat reliable control.
It is also known that 3,5-bis(trifluoromethyl)benzoyl fluorides can be prepared by selectively hydrolyzing 1,3,5-tris(trichloromethyl)benzenes with water to give 3,5-bis(trichloromethyl)benzoyl chlorides (see German Patent Specification 705,650) and then carrying out a complete chlorine/fluorine exchange with hydrogen fluoride or antimony trifluoride (see German Patent Specification 707,955). Whether and, where appropriate, how the corresponding benzoyl chlorides (xe2x80x9cBTBsxe2x80x9d) can be obtained from 3,5-bis-(trifluoromethyl)-benzoyl fluorides is not known.
There is therefore a need for a process for the preparation of BTBs that can be reliably carried out on an industrial scale without particular complexity and that starts from readily accessible starting materials.
We have now found a process for the preparation of 3,5-bis(trifluoromethyl)benzoyl chlorides of formula (I) 
wherein
X is hydrogen, fluorine, or chlorine, comprising
(1) converting 3,5-dimethylbenzoic acids of formula (V) 
wherein
X has the meaning given for formula (I),
into the corresponding acid chlorides of formula (IV) 
wherein
X has the meaning given for formula (I),
(2) completely free-radically chlorinating the acid chlorides of formula (IV) in the side chains to give 3,5-bis(trichloromethyl)benzoyl chlorides of formula (III) 
wherein
X has the meaning given for formula (I),
(3) fluorinating the 3,5-bis(trichloromethyl)benzoyl chlorides of formula (III) with anhydrous hydrogen fluoride and/or antimony pentafluoride to give 3,5-bis(trifluoromethyl)benzoyl fluorides of formula (II) 
wherein
X has the meaning given for formula (I), and
(4) reacting the 3,5-bis(trifluoromethyl)benzoyl fluorides of formula (II) with silicon tetrachloride in the presence of a further Lewis acid to give the compounds of formula (I).
In formulas (I) to (V), X is preferably hydrogen.
The first stage of the process according to the invention, the preparation of the acid chlorides of the formula (IV) from the benzoic acids (V), can be carried out analogously to known processes for the preparation of carbonyl chlorides from carboxylic acids. One possibility for the reaction of 3,5-dimethylbenzoic acid with phosphorus pentachloride is known from Can. J. Chem., 41, 2962 (1963) and another with thionyl chloride is known from J. Org. Chem., 24, 1301 (1959). These reactions can be carried out analogously for compounds in which X is fluorine or chlorine. The benzoic acids of the formula (V) required to carry out the first stage can be prepared by known processes or analogously thereto. 3,5-Dimethylbenzoic acid is commercially available.
The conversion to the acid halides of the formula (IV) can be carried out with chlorinating reagents, for example, with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or phosgene. Preference is given to using thionyl chloride or oxalyl chloride, the reaction products of which (hydrogen chloride and sulfur dioxide or hydrogen chloride, carbon monoxide and carbon dioxide respectively) are readily volatile and therefore can be removed easily.
The conversion to the acid chlorides of formula (IV) is preferably carried out in the presence of a diluent. Suitable for this purpose are inert organic solvents or mixtures thereof. By way of example, mention may be made of aliphatic, alicyclic, and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylenes and Decalin, halogenated hydrocarbons, such as chlorobenzene, dichlorobenzenes, methylene chloride, chloroform, tetrachloromethane, dichloroethane, trichloroethane and tetrachloroethylene, ethers, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether and anisole, esters, such as methyl acetate, ethyl acetate and butyl acetate, and sulfones, such as sulfolane. Per mole of benzoic acid of the formula (V), 50 to 150 ml of diluent, for example, can be used.
It is advantageous to use an excess of the chlorinating reagent, for example, 1.1 to 10 mol (preferably 1.2 to 3 mol) of chlorinating reagent per mole of the benzoic acid of the formula (V).
The reaction temperature for this stage can be varied within a relatively wide range. For example, it can be between 0 and 150xc2x0 C., preferably between 20 and 120xc2x0 C.
The work-up following the reaction can, for example, be carried out by distillation. If the preferred chlorinating reagents are used, it is possible to readily distill off their excess and the diluent which may be present, and to use the distillation residue as crude product in the next stage.
The second stage of the process according to the invention, the side-chain chlorination of the 3,5-dimethylbenzoyl chlorides of the formula (IV), is novel. This side-chain chlorination is carried out as a free-radical reaction. This can be achieved as a result of elevated temperature, irradiation by a light source, and/or addition of a free-radical initiator. Examples of suitable light sources are incandescent lamps, preferably halogen lamps and medium- and high-pressure mercury vapour lamps. Suitable free-radical initiators are, for example, benzoyl peroxide, di-tert-butyl peroxide, 2,2-aza-bis(isobutyronitrile), and 2-phenylazo-2,4-dimethyl-4-methoxy-valeronitrile. Preference is given to using a light source at elevated temperature. The reaction temperature can, for example, be between 80 and 250xc2x0 C., preferably 100 to 220xc2x0 C., particularly preferably between 110 and 190xc2x0 C. Here, it is advantageous to start the chlorination at relatively low temperatures, for example, 80 to 140xc2x0 C., and to continue to the end at relatively high temperatures, for example, 160 to 250xc2x0 C.
The chlorinating agent used in this stage is generally elemental chlorine.
Per mole of dimethylbenzoyl chloride of the formula (IV), it is possible, for example, to use 6.3 to 18 mol (preferably 7.2 to 12 mol) of chlorine gas.
For work-up after the reaction it is possible to displace any excess chlorine, e.g., by introducing an inert gas, such as nitrogen, or by applying a vacuum. Crude product obtainable in this way can be used directly in the next reaction stage, although, if desired, it can also be purified, e.g., by vacuum distillation.
The third stage of the process according to the invention is the fluorination of the 3,5-bis(trichloromethyl)benzoyl chlorides of the formula (III) to give the 3,5-bis(trifluoromethyl)benzoyl fluorides of the formula (II). One possibility for the preparation of the 3,5-bis(trifluoromethyl)benzoyl fluoride is already known from German Patent Specification 707,955 and can be transferred analogously to the compounds in which X is fluorine or chlorine.
The fluorination is carried out with anhydrous hydrofluoric acid and/or antimony pentafluoride. In some instances, catalysts may be added, e.g., Lewis acids, such as titanium tetrachloride, boron trichloride, or antimony pentafluoride, which generally increases the rate of the reaction. Preference is given to using anhydrous hydrogen fluoride in a mixture with titanium tetrachloride. It is also possible to add the Lewis acids after the reaction has started.
Per mole of benzoyl chloride of the formula (III), it is possible to use, for example, 7.7 to 21 mol (corresponding to a 10 to 200% excess) of anhydrous hydrogen fluoride or the corresponding amount of antimony pentafluoride and, for example, 0 to 0.2 mol of Lewis acids.
The fluorination can be carried out, for example, by starting at a temperature below the boiling point (at atmospheric pressure) of hydrogen fluoride, for example, at xe2x88x9220 to +15xc2x0 C., and, to complete the reaction, continuing to the end at relatively high temperatures, for example, at 100 to 180xc2x0 C. As the result of the vapor pressure of the hydrogen fluoride, pressures up to 100 bar can arise here, which necessitates the use of reaction vessels which are appropriately pressure-resistant. The hydrogen chloride liberated is decompressed, for example, at temperatures above +20xc2x0 C. via a pressure relief valve.
The reaction mixture that is present following the fluorination can be worked up by fractional distillation, for example.
The final fourth stage of the process according to the invention is the chlorine/fluorine exchange at the carbonyl group, which has hitherto not been disclosed for these compounds. This is carried out using silicon tetrachloride as reagent in the presence of a further Lewis acid, for example, aluminum chloride, boron trifluoride, titanium tetrachloride, iron trichloride, or mixtures thereof.
Per mole of benzoyl fluoride of the formula (II), it is possible, for example, to use 0.25 to 1 mol (1 to 4 equivalents), preferably 0.3 to 0.5 mol, of silicon tetrachloride, and 0.01 to 0.1 mol, preferably 0.02 to 0.05 mol, of further Lewis acid.
This chlorine/fluorine exchange can, for example, be carried out at temperatures between 0 and 70xc2x0 C., preferably between 20 and 50xc2x0 C. The procedure here may involve initially introducing the further Lewis acid either with the benzoyl fluoride of the formula (II) or with the silicon tetrachloride and metering in the other component in each case. In this way, the evolution of gas can be controlled easily.
The reaction mixture which is present following the chlorine/fluorine exchange can be worked up, for example, by firstly separating off the solid constituents, e.g., by filtration, preferably following the addition of a filtration auxiliary, such as cellulose or a zeolite. By fractional vacuum distillation of the filtrate it is possible to obtain the prepared BTB in pure form. To deactivate residues of the silicon tetrachloride and/or the further Lewis acid, it may be advantageous to add a small amount of an aryl- or alkylphosphine, for example, 0.1 to 1% by weight, to the mixture to be distilled. Triphenylphosphine, for example, is suitable for this purpose.
Using the process according to the invention, BTBs of the formula (I) can be prepared in good yields from the readily accessible 3,5-dimethylbenzoic acids of the formula (V) in a process which can be readily and easily carried out on an industrial scale. Viewed over all reaction stages, the yield is significantly greater than 60% of theory.
Some of the compounds of the formulas (I) to (IV) are novel. The present invention therefore also relates to 3,5-bis(trifluoromethyl)benzoyl chlorides of the formula (Ia) 
in which
Xxe2x80x2 is fluorine or chlorine,
3,5-bis(trifluoromethyl)benzoyl fluorides of the formula (IIa) 
in which
Xxe2x80x2 is fluorine or chlorine,
3,5-bis(trichloromethyl)benzoyl chlorides of the formula (IIIa) 
in which
Xxe2x80x2 is fluorine or chlorine, and
3,5-dimethylbenzoyl chlorides of the formula (IVa) 
in which
Xxe2x80x2 is fluorine or chlorine.
The preparation of compounds of the formulas (Ia) to (IVa) is described above. They are novel intermediates for the advantageous preparation of 3,5-bis(trifluoromethyl)benzoyl chloride by the process according to the invention.